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NFAT蛋白在肥大细胞白细胞介素13基因转录中的作用。

Role of NFAT proteins in IL13 gene transcription in mast cells.

作者信息

Monticelli Silvia, Solymar Deborah C, Rao Anjana

机构信息

Department of Pathology, Harvard Medical School, and CBR Institute for Biomedical Research, Boston, MA 02115, USA.

出版信息

J Biol Chem. 2004 Aug 27;279(35):36210-8. doi: 10.1074/jbc.M406354200. Epub 2004 Jun 30.

Abstract

Th2 and mast cells are participants in the asthmatic response to allergens, and both cell types produce the cytokines interleukin (IL)-4 and IL-13. IL-13 in particular is both necessary and sufficient for experimental models of asthma. The transcription factor NFAT plays a central role in cytokine transcriptional regulation in both cell types. Here, we analyze the molecular basis of IL13 gene transcription in Th2 and mast cells. We show that NFAT1 is the major NFAT protein involved in regulating IL13 transcription in mast cells. Although NFAT2 is correctly expressed and regulated in mast cells, it does not contribute to IL13 gene transcription as shown by analysis of cells lacking NFAT2 and cells expressing a constitutively active version of NFAT2. The difference between NFAT1 and NFAT2 appears to be due to a preferential synergistic interaction of NFAT1 with GATA proteins at the IL13 promoter. We suggest that mast cells lack a co-activator protein that stabilizes the binding of NFAT2 to the IL13 promoter by interacting either with NFAT2 itself or with a DNA-bound complex of NFAT2 and GATA proteins.

摘要

Th2细胞和肥大细胞参与了对过敏原的哮喘反应,这两种细胞类型都会产生细胞因子白细胞介素(IL)-4和IL-13。特别是IL-13在哮喘实验模型中既是必需的也是充分的。转录因子NFAT在这两种细胞类型的细胞因子转录调控中起着核心作用。在此,我们分析了Th2细胞和肥大细胞中IL13基因转录的分子基础。我们表明,NFAT1是参与调节肥大细胞中IL13转录的主要NFAT蛋白。尽管NFAT2在肥大细胞中正确表达并受到调控,但通过对缺乏NFAT2的细胞和表达组成型活性NFAT2的细胞的分析表明,它对IL13基因转录没有贡献。NFAT1和NFAT2之间的差异似乎是由于NFAT1与IL13启动子处的GATA蛋白优先发生协同相互作用。我们认为肥大细胞缺乏一种共激活蛋白,该蛋白通过与NFAT2本身或与NFAT2和GATA蛋白的DNA结合复合物相互作用来稳定NFAT2与IL13启动子的结合。

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